ETV7 represses a subset of interferon-stimulated genes that restrict influenza viruses

The type I interferon (IFN) response is an important component of the innate immune response to viral infection. Precise control of interferon responses is critical, as insufficient levels of interferon-stimulated genes (ISGs) can lead to a failure to restrict viral spread, while excessive ISG activation results in interferon-related pathologies. While both positive and negative regulatory factors can control the magnitude and duration of IFN signaling, it is also appreciated that a number of ISGs regulate aspects of the interferon response themselves. However, the mechanisms underlying complex ISG regulatory networks remain incompletely defined. In this study, we performed a CRISPR activation screen to identify new regulators of type I IFN responses. We identified ETS variant transcription factor 7 (ETV7), a strongly induced ISG, as a protein that acts as a negative regulator of the type I IFN response; however, ETV7 did not uniformly suppress ISG transcription. Instead, ETV7 specifically targeted a subset of ISGs for regulation based on their promoter sequences. We further showed the subset of ETV7-modulated ISGs is particularly important for control of influenza viruses. Together, our data demonstrate that ETV7 is a component of the complex ISG regulatory network by controlling the expression of a subset of ISGs with a potential role in directing the interferon response against specific viruses.